Congenic strains are routinely used for positional mapping of quantitative trait loci; while conplastic strains, derived by substitution of different mitochondrial genomes on the same nuclear genetic background of inbred rodent strains, provide a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Derivation of congenic or conplastic strains using a traditional backcross breeding strategy (10 backcrosses) takes more than 3 years. There are two principal strategies to speed up this process: (1) marker-assisted derivation of "speed" congenic/conplastic strains and (2) derivation of "supersonic" congenic/conplastic strains using in each backcross generation embryos obtained from 4-week-old superovulated females; thus, each backcross generation takes only 7 weeks. Both strategies could also be combined. In the current chapter, a method for derivation of "supersonic" congenic/conplastic rat strains is described.

• MeSH
• genotyp MeSH
• inbrední kmeny potkanů genetika   MeSH
• indukce ovulace metody   MeSH
• krysa rodu rattus MeSH
• potkani inbrední BN genetika   MeSH
• potkani inbrední SHR genetika   MeSH
• přenos embrya metody   MeSH
• zvířata kongenní genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

• MeSH
• histokompatibilita MeSH
• isoantigeny MeSH
• krysa rodu rattus MeSH
• protilátky MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• cytotoxické testy imunologické MeSH
• histokompatibilita MeSH
• isoantigeny MeSH
• krysa rodu rattus MeSH
• lymfocyty MeSH
• protilátky MeSH
• Check Tag
• krysa rodu rattus MeSH

Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18-28 mmHg difference) and diastolic (10-15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome.

• MeSH
• genom MeSH
• glukózový toleranční test MeSH
• hemodynamika MeSH
• lidé MeSH
• lidské chromozomy, pár 16 genetika   MeSH
• metabolický syndrom genetika   metabolismus   patofyziologie   MeSH
• metabolom MeSH
• potkani inbrední BN genetika   metabolismus   fyziologie   MeSH
• potkani inbrední SHR genetika   metabolismus   fyziologie   MeSH
• zvířata kongenní genetika   metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We have developed a new, double-congenic rat strain BN-Lx.SHR2, which carries two distinct segments of chromosome 2 introgressed from the spontaneously hypertensive rat strain (SHR) into the genetic background of congenic strain BN-Lx, which was previously shown to express variety of metabolic syndrome features. In 16-wk-old male rats of BN-Lx and BN-Lx.SHR2 strains, we compared their glucose tolerance and triacylglycerol and cholesterol concentrations in 20 lipoprotein subfractions and the lipoprotein particle sizes under conditions of feeding standard and high-sucrose diets. Introgression of two distinct SHR-derived chromosome 2 segments resulted in decreased adiposity together with aggravation of glucose intolerance in the double-congenic strain. The BN-Lx.SHR2 rats were more sensitive to sucrose-induced rise in triacylglycerolemia. Although the total cholesterol concentrations of the two strains were comparable after the standard diet and even lower in BN-Lx.SHR2 after sucrose feeding, detailed analysis revealed that under both dietary conditions, the double-congenic strain had significantly higher cholesterol concentrations in low-density lipoprotein fractions and lower high-density lipoprotein fractions. We established a new inbred model showing dyslipidemia and mild glucose intolerance without obesity, attributable to specific genomic regions. For the first time, the chromosome 2 segments of SHR origin are shown to influence other than blood pressure-related features of metabolic syndrome or to be involved in relevant nutrigenomic interactions.

• MeSH
• cholesterol analýza   MeSH
• financování organizované MeSH
• genomika MeSH
• hypertenze genetika   krev   patologie   MeSH
• krysa rodu rattus MeSH
• lipoproteiny chemie   krev   MeSH
• lokus kvantitativního znaku MeSH
• modely nemocí na zvířatech MeSH
• porucha glukózové tolerance genetika   MeSH
• potkani inbrední SHR genetika   MeSH
• sacharosa farmakologie   MeSH
• savčí chromozomy MeSH
• triglyceridy analýza   MeSH
• tuková tkáň fyziologie   MeSH
• zvířata kongenní MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

OBJECTIVES: Ondansetron is an antagonist of 5-HT3 receptors mostly used as an antiemetic yet known to modulate metabolism and appetite. We tested the metabolic effects of ondansetron in newly derived congenic rat strain, carrying limited chromosome 8 regions of (PD) Brown Norway (BN) and polydactylous (PD) strain origins (including variant serotonin receptor Htr3b gene) within the genomic background of highly inbred model of metabolic syndrome, the spontaneously hypertensive rat (SHR). METHODS: Adult, standard diet-fed male rats of SHR and the congenic SHR.(PD/BN)8 strains received ondansetron (2mg/kg body weight/day) or vehicle (n=6/strain/treatment) via oral gavage for 14 days while we followed their metabolic and morphometric profiles including glucose tolerance and triacylgycerol and cholesterol concentrations in 20 lipoprotein fractions. RESULTS: We fine-mapped the chromosome 8 differential segment in the new SHR.(PD/BN)8 congenic strain: it comprises BN-derived region together with an adjacent 422kb stretch of PD origin. The SHR.(PD/BN)8 rats were heavier than SHR, the fasting glucose was significantly higher in ondansetron-treated congenic than in SHR (post-hoc Tukey's HSD p=0.02). Compared to SHR, ondansetron induced significantly more robust increases of cholesterol and triacylglycerol concentrations in total, chylomicron, VLDL and HDL particles in the SHR.(PD/BN)8 congenic strain. CONCLUSION: We established new congenic model with distinct pharmacogenetic profile related to metabolic effects of ondansetron, facilitating thus the search for responsible genetic variants within the limited genomic region demarcated by the differential segment.

• MeSH
• hypertenze farmakoterapie   genetika   metabolismus   MeSH
• krysa rodu rattus MeSH
• lipidy krev   MeSH
• metabolický syndrom farmakoterapie   genetika   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• ondansetron farmakologie   MeSH
• polydaktylie genetika   MeSH
• porucha glukózové tolerance farmakoterapie   genetika   metabolismus   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR * MeSH
• receptory serotoninové 5-HT3 genetika   metabolismus   MeSH
• savčí chromozomy MeSH
• serotoninové receptory 5-HT3 - antagonisté farmakologie   MeSH
• zvířata kongenní MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: All-trans retinoic acid (ATRA, tretinoin) is a vitamin A derivative commonly used in the treatment of diverse conditions ranging from cancer to acne. In a fraction of predisposed individuals, the administration of ATRA is accompanied by variety of adverse metabolic effects, particularly by the induction of hyperlipidemia. We have previously derived a minimal congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strain sensitive to ATRA-induced increase of triacylglycerols and cholesterol under condition of high-sucrose diet. SHR-Lx differs only by 7 genes of polydactylous rat (PD/Cub) origin from its spontaneously hypertensive rat (SHR) progenitor strain. METHODS: Adult male rats of SHR and SHR-Lx strains were fed standard diet (STD) and experimental groups were subsequently treated with ATRA (15 mg/kg) via oral gavage for 16 days, while still on STD. We contrasted the metabolic profiles (including free fatty acids, triacylglycerols (TG) and cholesterol (C) in 20 lipoprotein fractions) between SHR and SHR-Lx under conditions of standard diet and standard diet + ATRA. We performed transcriptomic analysis of muscle tissue (m. soleus) in all groups using Affymetrix GeneChip Rat Gene 2.0 ST Arrays followed by Ingenuity Pathway Analysis and real-time PCR validation. RESULTS: In response to ATRA, SHR-Lx reacted with substantially greater rise in TG and C concentrations throughout the lipoprotein spectrum (two-way ANOVA strain * RA interaction significant for C content in chylomicrons (CM), VLDL and LDL as well as total, CM and HDL-TG). CONCLUSIONS: According to our modeling of metabolic and signalization pathways using differentially expressed genes we have identified a network with major nodes (including Sirt3, Il1b, Cpt1b and Pparg) likely to underlie the observed strain specific response to ATRA.

• MeSH
• dyslipidemie krev   chemicky indukované   genetika   MeSH
• kosterní svaly metabolismus   MeSH
• lipidy krev   MeSH
• metabolismus lipidů MeSH
• potkani inbrední SHR MeSH
• transkriptom * MeSH
• tretinoin MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• inbrední kmeny potkanů MeSH
• krysa rodu rattus MeSH
• syndrom krátkého žebra a polydaktylie genetika   chemicky indukované   MeSH
• teratogeny MeSH
• thalidomid škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

Congenic strains with the polydactyly-luxate syndrome (PLS), the BN.lx and Lew.lx, were originally derived to study the expression and mode of inheritance of the lx mutant gene on rat chromosome 8. The BN.lx PLS congenic strain together with the spontaneously hypertensive SHR strain served as progenitors for the production of the HXB/BXH recombinant inbred (RI) strains. One of the RI strains, the BXH11, carrying PLS was used for the transfer of PLS determining lx allele onto the SHR strain genetic background. Using PCR analysis, differential segments of chromosome 8 of BN.lx and SHR.lx congenic strains were described and shown to carry also genes associated with blood pressure and plasma triglyceride regulation. Possible experimental exploitation of chromosome 8 congenic strains in these respects is thus discussed.

• MeSH
• chromozomy MeSH
• hypotenze MeSH
• krevní tlak * MeSH
• krysa rodu rattus MeSH
• modely genetické MeSH
• modely nemocí na zvířatech MeSH
• mutantní kmeny potkanů * genetika   MeSH
• polydaktylie MeSH
• potkani inbrední BN MeSH
• potkani inbrední LEW MeSH
• potkani inbrední SHR MeSH
• triglyceridy * krev   MeSH
• vrozené deformity končetin * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• abnormality vyvolané léky MeSH
• genotyp MeSH
• inbrední kmeny potkanů MeSH
• krysa rodu rattus MeSH
• plod abnormality   účinky léků   MeSH
• polydaktylie etiologie   MeSH
• teratogeny MeSH
• tretinoin škodlivé účinky   MeSH
• vývoj plodu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH